PLK4: a link between centriole biogenesis and cancer

ABSTRACT

Introduction: Polo like kinase (PLK) is known to play a pivotal role in various cell cycle processes to perpetuate proper division and growth of the cells. Polo like kinase-4 (PLK4) is one such kinase that appears in low abundance and plays a well-characterized role in centriole duplication. PLK4 deregulation (i.e. both overexpression and depletion of PLK4), leads to altered mitotic fidelity and thereby triggers tumorigenesis. Hence, over the last few years PLK4 has emerged as a potential therapeutic target for the treatment of various advanced cancers.

Areas covered: In this review, we discuss the basic structure, expression, localization and functions of PLK4 along with its regulation by various proteins. We also discuss the role of altered PLK4 activity in the onset of cancer and the current pre-clinical and clinical inhibitors to regulate PLK4.

Expert opinion: PLK4 mediated centriole duplication has a crucial role in maintaining mitotic correctness in normal cells, while its deregulation has a greater impact on genesis of cancer. Henceforth, a deep knowledge of the PLK4 levels, its role and interactions with various proteins in cancer is required to design effective inhibitors for clinical use.

KEYWORDS:

• PLK4
• centriole duplication
• CFI-400
• 945

Article highlights

• PLK4 is a serine/threonine kinase that plays a critical role in centriole duplication.

• PLK4 shows predominant localization in the centriole and is involved in placental development, DNA damage response, spindle assembly, ciliogenesis, cytokinesis and mitotic exit.

• PLK4 autoregulates its own stability via SCF/β-TRCP E3 ubiquitin ligase complex.

• Deregulated PLK4 activity plays a prominent role in cancer and metastasis.

• Several PLK4 inhibitors with anticancer activity are in pre-clinical stage and a single inhibitor, CFI-400945 has entered clinical phase.

• Further research should focus on finding safer and more effective drugs at clinical stage, based on a better understanding of PLK4.

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Declaration of interest

The authors are all employees of Jubilant Biosys Ltd. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

This paper is funded by Jubilant Biosys Ltd.